Clinical diagnostics laboratories help healthcare professionals worldwide monitor the health and disease states of patients. These laboratories employ procedures to measure the concentration of one or more analytes, such as salts, sugars, proteins, hormones, or dissolved gasses, in a sample of tissue or bodily fluid obtained from an individual patient. The measured concentration of an analyte is compared with a threshold or range that distinguishes between normal and abnormal concentrations for the patient, with respect to the population to which the patient belongs. Based upon the comparison, additional tests can be prompted or a diagnosis for the patient can be made.
To ensure that analytical procedures are used to make accurate diagnoses, these procedures are calibrated with calibrators containing known and/or reproducible concentrations of certain analytes. For example, several calibrators containing different levels of an analyte can be used to construct a response curve of a particular instrument for that analyte. The concentration of the analyte in a patient sample can then be determined on the instrument by measuring the sample and interpolating along the response curve. Quality controls can also be used to test whether analyte concentrations reported by an instrument are consistent over time. An instrument can be tested periodically (e.g., daily or weekly) with a control and the historical distribution of reported analyte concentrations can be examined, for example using Levey-Jennings charts or Westgard rules. If a control measurement deviates significantly from recent measurements or the historical mean, then measurements of patient samples can be discontinued until the instrument can be serviced or recalibrated. Control measurements can be shared among laboratories to ensure that different instruments of the same design provide consistent results when used to detect the same analyte.
Commercially available quality controls are typically prepared by spiking one or more analytes into a base matrix containing various additives such as stabilizers and antimicrobial agents. Base matrices can be manufactured from processed human bodily fluids, such as urine or serum, to ensure similarity between the quality controls and patient samples. When multiple analytes are present, they can be for related medical conditions (for example, markers for different tumors) or detectable by the same method (for example, photometry). Quality controls are typically offered in bi-level or tri-level configurations to monitor and challenge the performance of a measurement procedure at analyte concentrations above, near, and/or below a decision threshold. Quality control materials are designed to be stable and cost-effective, and should provide lot-to-lot reproducibility for analyte test results.
Once a quality control for an analyte is prepared, a ‘recovery’ or reported concentration for the analyte can be determined by the end user or control manufacturer. The recovery is particular to the instrument or measurement procedure to which the control is applied, and can be stated as a mean or range. In the case of ‘unassayed’ controls, the end user determines recoveries using his or her own laboratory procedures or nationally or internationally recognized protocols, such as Clinical and Laboratories Standards Institute document C24-A33. Such protocols can involve testing the control on an instrument repeatedly over a short period of time (for example, 20 data points over two to three weeks) and computing the mean and standard deviation of recoveries measured during this time. For ‘assayed’ controls, the manufacturer provides expected means and ranges of recoveries for all analytes included in the control for one or more procedures. For this purpose, the control manufacturer tests a sufficiently large sample of each product lot with the measurement procedures to establish a statistically valid mean and standard deviation for the analyte at each level provided (FDA Guidance Document—Points to Consider Document on Assayed and Unassayed Quality Control Material, Draft Release Feb. 3, 1999). End users can also establish means and ranges for recoveries of assayed controls based on their own protocols prior to using the controls to monitor the performance of their test methods.
When a quality control is tested using multiple clinical diagnostic measurement procedures, the procedures can yield different recoveries for the same analyte. The differences can be due to differences or lack of standardization in assay architectures, detection technologies, or various parameters of the procedures. These differences can be difficult to reconcile, especially when no absolute standards for the analyte exist to provide well-known or ‘true’ concentrations. As a result, separate recovery ranges or thresholds must be established for each measurement procedure to identify normal and abnormal concentrations of the analyte in patient samples. The task of establishing these recoveries can be made more difficult when the concentrations of an analyte that are considered normal or abnormal vary. For example, one patient can be expected to have a higher concentration of an analyte in his or her bodily fluid than another patient, due to differences in the patients' ages, weights, ethnicities, general physiological states, or other factors. Thus, to make consistent diagnoses for many patients using multiple measurement procedures, recoveries of these procedures for the analyte often must be established at more than just two or three analyte levels.
Different diagnostic procedures often have different measurement ranges for a given analyte, and exhibit other differences in performance in terms of precision, accuracy, limits of quantitation (LOQ), limits of detection (LOD), or linearity. As a result, the procedures may not be amenable to monitoring with a common set of pre-prepared quality controls. Commercially available controls, for example those from Randox Laboratories Ltd. and Thermo Scientific, may not provide an analyte of interest in the concentrations needed to monitor all widely used diagnostic procedures for that analyte. Many instrument manufacturers provide their own quality controls for analytes to which their instruments are sensitive. But the controls for one instrument may not be usable on a competing instrument, again due to differences in instrument performance characteristics or detection technologies. In addition, the controls available from an instrument manufacturer may not contain a particular combination of analytes and other components found in a patient sample of interest.
Customizable quality controls are described in co-assigned U.S. Pat. No. 9,354,144, entitled “Customized Quality Controls for Analytical Assays” and issued on May 31, 2016, which is incorporated herein by reference. These quality controls can be prepared by dissolving one or more beads, each containing one or more analytes, in a liquid base matrix. By selecting the number of beads and the volume of base matrix, any desired analyte concentration can be obtained. Other desired components can be introduced into a control as part of the bead or matrix. With enough beads and base matrix, any number of controls corresponding to two, three, or more targeted analyte levels can be prepared. Customizable quality controls can thus be prepared according to the end user's needs and used to monitor any diagnostic procedure. Recoveries for these controls measured with different procedures can be compared.